Critical Role for Interleukin-1β (IL-1β) during Chlamydia muridarum Genital Infection and Bacterial Replication-Independent Secretion of IL-1β in Mouse Macrophages

Recent findings have implicated interleukin-1 beta (IL-1 beta) as an important mediator of the inflammatory response in the female genital tract during chlamydial infection. But how IL-1 beta is produced and its specific role in infection and pathology are unclear. Therefore, our goal was to determine the functional consequences and cellular sources of IL-1 beta expression during a chlamydial genital infection. In the present study, IL-1 beta(-/-) mice exhibited delayed chlamydial clearance and decreased frequency of hydrosalpinx compared to wild-type (WT) mice, implying an important role for IL-1 beta both in the clearance of infection and in the mediation of oviduct pathology. At the peak of IL-1 beta secretion in WT mice, the major producers of IL-1 beta in vivo are F4/80(+) macrophages and GR-1(+) neutrophils, but not CD45(-) epithelial cells. Although elicited mouse macrophages infected with Chlamydia muridarum in vitro secrete minimal IL-1 beta, in vitro prestimulation of macrophages by Toll-like receptor (TLR) ligands such as lipopolysaccharide (LPS) purified from Escherichia coli or C. trachomatis L2 prior to infection greatly enhanced secretion of IL-1 beta from these cells. By using LPS-primed macrophages as a model system, it was determined that IL-1 beta secretion was dependent on caspase-1, potassium efflux, and the activity of serine proteases. Significantly, chlamydia-induced IL-1 beta secretion in macrophages required bacterial viability but not growth. Our findings demonstrate that IL-1 beta secreted by macrophages and neutrophils has important effects in vivo during chlamydial infection. Additionally, prestimulation of macrophages by chlamydial TLR ligands may account for the elevated levels of pro-IL-1 beta mRNA observed in vivo in this cell type.